Funding Translational Medicine via Public Markets: The Business Development Company

A business development company (BDC) is a type of closed-end investment fund with certain relaxed requirements that allow it to raise money in the public equity and debt markets, and can be used to fund multiple early-stage biomedical ventures, using financial diversification to de-risk translational medicine. By electing to be a “Regulated Investment Company” for tax purposes, a BDC can avoid double taxation on income and net capital gains distributed to its shareholders. BDCs are ideally suited for long-term investors in biomedical innovation, including: (i) investors with biomedical expertise who understand the risks of the FDA approval process, (ii) “banking entities,” now prohibited from investing in hedge funds and private equity funds by the Volcker Rule, but who are permitted to invest in BDCs, subject to certain restrictions, and (iii) retail investors, who traditionally have had to invest in large pharmaceutical companies to gain exposure to similar assets. We describe the history of BDCs, summarize the requirements for creating and managing them, and conclude with a discussion of the advantages and disadvantages of the BDC structure for funding biomedical innovatio

Digital Word-of-Mouth and the Gender Implications

Consumers can now easily access data and exchange sentiments regarding products and services on an unprecedented scale, and often in real time, through digital connections. The Internet and mobile technologies have made sharing of information and opinions among consumers easier than ever. The capacity of online participants to inspire and transform perspectives has been touted to surpass the radical potency of television when it entered the consumer’s province during the 50’s. Men and women use social media sites to learn about new products, to become smarter shoppers and to feel good about a purchase they might have already made. College students are so driven to continuously connect that they chain themselves to the technology 24/7. As digital natives, they are so thoroughly immersed in the process that they possess an indigenous aptitude to operate and fully function within the techno world. Marketers have long recognized the prominent role that word-of-mouth communication (WOM) played in the consumer decision-making process. However, in recent years, interest has grown with the expansion in the number and types of communication channels offered by new technologies. Online WOM has established itself as a central element in the lives of consumers. In the view of many, the power of social media and online digital WOM communications outstrips the ability of companies to shape their own messages through either traditional communication means or by way of their own social media initiatives. Common wisdom now holds that companies that ignore consumer-to-consumer information posted about their business and products do so at their own peril. This study explored the implication of gender on the use of digital WOM along with specific online behavior characteristics and purchase variances of male and female digital activities. Research findings suggest the identification of primary digital WOM leaders as revealed through purchase behavior, shopping experience, purchase confidence and innovative online conduct. The concept that “tie-strength” is an indicator of the importance of a moderator’s impact on consumer purchase decisions (Brown & Reingen 1987) may be shifting in regard to online digital WOM. This study indicates that respondents were neutral in regard to the usefulness of online digital WOM compared to friends and family. While online was not deemed as more useful, the neutrality indicates that more research needs to be done on the concept of tie-strength as well as outside indicators of online digital WOM credibility

Rationale, Study Design, and Cohort Characteristics for the Markers for Environmental Exposures (MEE) Study.

Environmental factors have been linked to many diseases and health conditions, but reliable assessment of environmental exposures is challenging. Developing biomarkers of environmental exposures, rather than relying on self-report, will improve our ability to assess the association of such exposures with disease. Epigenetic markers, most notably DNA methylation, have been identified for some environmental exposures, but identification of markers for additional exposures is still needed. The rationale behind the Markers for Environmental Exposures (MEE) Study was to (1) identify biomarkers, especially epigenetic markers, of environmental exposures, such as pesticides, air/food/water contaminants, and industrial chemicals that are commonly encountered in the general population; and (2) support the study of potential relationships between environmental exposures and health and health-related factors. The MEE Study is a cross-sectional study with potential for record linkage and follow-up. The well-characterized cohort of 400 postmenopausal women has generated a repository of biospecimens, including blood, urine, and saliva samples. Paired data include an environmental exposures questionnaire, a breast health questionnaire, dietary recalls, and a food frequency questionnaire. This work describes the rationale, study design, and cohort characteristics of the MEE Study. In addition to our primary research goals, we hope that the data and biorepository generated by this study will serve as a resource for future studies and collaboration

Matched-Cohort Analysis of Autologous Hematopoietic Cell Transplantation with Radioimmunotherapy versus Total Body Irradiation–Based Conditioning for Poor-Risk Diffuse Large Cell Lymphoma

We conducted a matched-cohort analysis of autologous transplant conditioning regimens for diffuse large cell lymphoma in 92 patients treated with either radioimmunotherapy (RIT) or total body irradiation (TBI)–based conditioning regimens. The RIT regimen consisted of 0.4 mCi/kg of 90Y-ibritumomab tiuxetan plus BEAM (BCNU, etoposide, cytarabine, melphalan). The TBI-based regimen combined fractionated TBI at 1200 cGy, with etoposide and cyclophosphamide. Five factors were matched between 46 patient pairs: age at transplant ±5 years, disease status at salvage, number of prior regimens, year of diagnosis ±5 years, and year of transplantation ±5 years. Patients in the TBI group had higher rates of cardiac toxicity and mucositis, whereas Z-BEAM patients had a higher incidence of pulmonary toxicity. Overall survival at 4 years was 81.0% for the Z-BEAM and 52.7% for the TBI group (P = .01). The 4-year cumulative incidence of relapse/progression was 40.4% and 42.1% for Z-BEAM and TBI, respectively (P = .63). Nonrelapse mortality was superior in the Z-BEAM group: 0% compared with 15.8% for TBI at 4 years (P < .01). Our data demonstrate that RIT-based conditioning had a similar relapse incidence to TBI, with lower toxicity, resulting in improved overall survival, particularly in patients with ≥2 prior regimens

Accumulated dose to the rectum, measured using dose-volume histograms and dose-surface maps, is different from planned dose in all patients treated with radiotherapy for prostate cancer.

OBJECTIVE: We sought to calculate accumulated dose (DA) to the rectum in patients treated with radiotherapy for prostate cancer. We were particularly interested in whether dose-surface maps (DSMs) provide additional information to dose-volume histograms (DVHs). METHODS: Manual rectal contours were obtained for kilovoltage and daily megavoltage CT scans for 10 participants from the VoxTox study (380 scans). Daily delivered dose recalculation was performed using a ray-tracing algorithm. Delivered DVHs were summated to create accumulated DVHs. The rectum was considered as a cylinder, cut and unfolded to produce daily delivered DSMs; these were summated to produce accumulated DSMs. RESULTS: Accumulated dose-volumes were different from planned in all participants. For one participant, all DA levels were higher and all volumes were larger than planned. For four participants, all DA levels were lower and all volumes were smaller than planned. For each of these four participants, ≥1% of pixels on the accumulated DSM received ≥5 Gy more than had been planned. CONCLUSION: Differences between accumulated and planned dose-volumes were seen in all participants. DSMs were able to identify differences between DA and planned dose that could not be appreciated from the DVHs. Further work is needed to extract the dose data embedded in the DSMs. These will be correlated with toxicity as part of the VoxTox Programme. ADVANCES IN KNOWLEDGE: DSMs are able to identify differences between DA and planned dose that cannot be appreciated from DVHs alone and should be incorporated into future studies investigating links between DA and toxicity.JES is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. KH, MR and AMB are supported by the VoxTox Research Programme, which is funded by Cancer Research UK.This is the final version of the article. It first appeared from the British Institute of Radiology via http://dx.doi.org/10.1259/bjr.2015024

Increased Programmed Death-1 Molecule Expression in Cytomegalovirus Disease and Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

To study the role of the programmed death-1 molecule (PD-1) in cytomegalovirus (CMV) infection and disease after allogeneic hematopoietic cell transplantation (HCT), 206 subjects were followed prospectively for immune response to CMV and assigned to 3 groups based on CMV outcome. The subjects were analyzed retrospectively for PD-1 expression in cryopreserved CD4+ and CD8+T cells collected at days 40, 90, 120, 150, 180, and 360 posttransplantation. HCT recipients with CMV disease (n=14) were compared with recipients with prolonged CMV infection, but no CMV disease (median duration of infection, 3 months; n=14) and with controls with no CMV infection who received similar transplants (n=22). The CMV disease group had a significantly higher mean fluorescein intensity of PD-1 in CD4+ (P < .05) and CD8+ (P < .05) lymphocytes at all time points studied. PD-1 expression also was significantly elevated in those with severe acute graft-versus-host disease (aGVHD), including the no-viremia group. The data suggest that PD-1 is induced by aGVHD even in the absence of CMV infection. This enhanced PD-1 expression during severe aGVHD and with CMV reactivation could explain the known role of aGVHD as a risk factor for CMV disease

Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540

A Census of Baryons and Dark Matter in an Isolated, Milky Way-sized Elliptical Galaxy

We present a study of the dark and luminous matter in the isolated elliptical galaxy NGC720, based on deep X-ray observations made with Chandra and Suzaku. The gas is reliably measured to ~R2500, allowing us to place good constraints on the enclosed mass and baryon fraction (fb) within this radius (M2500=1.6e12+/-0.2e12 Msun, fb(2500)=0.10+/-0.01; systematic errors are <~20%). The data indicate that the hot gas is close to hydrostatic, which is supported by good agreement with a kinematical analysis of the dwarf satellite galaxies. We confirm a dark matter (DM) halo at ~20-sigma. Assuming an NFW DM profile, our physical model for the gas distribution enables us to obtain meaningful constraints at scales larger than R2500, revealing that most of the baryons are in the hot gas. We find that fb within Rvir is consistent with the Cosmological value, confirming theoretical predictions that a ~Milky Way-mass (Mvir=3.1e12+/-0.4e12 Msun) galaxy can sustain a massive, quasi-hydrostatic gas halo. While fb is higher than the cold baryon fraction typically measured in similar-mass spiral galaxies, both the gas fraction (fg) and fb in NGC720 are consistent with an extrapolation of the trends with mass seen in massive galaxy groups and clusters. After correcting for fg, the entropy profile is close to the self-similar prediction of gravitational structure formation simulations, as observed in galaxy clusters. Finally, we find a strong heavy metal abundance gradient in the ISM similar to those observed in massive galaxy groups.Comment: 23 pages, 13 figures, 4 tables. Accepted for publication in the Astrophysical Journal. Minor modifications to match accepted version. Conclusions unchange

‘The Rest is Silence’:Psychogeography, Soundscape and Nostalgia in Pat Collins’ Silence

Guy Debord defines the term psychogeography as 'the study of the precise laws and specific effects of the geographical environment, consciously organised or not, on the emotions and behaviour of individuals' (Debord 1955: 23). Similar to the belief of psychogeographers that the geography of an environment has a psychological effect on the human mind, proponents of acoustic ecology such as R. Murray Schafer hold that humans are affected by the sound of the environment in which they find themselves. Further to this, they examine the extent to which soundscapes can be shaped by human behaviour. Recently a body of Irish films has emerged that directly engages with the Irish soundscape and landscape on a psychogeographical level. Rather than using landscape as a physical space for the locus of action, these representations of the Irish landscape allow for an engagement with the aesthetic effects of the geographical landscape as a reflection of the psychological states of the protagonists. Bearing this in mind, this article examines how Silence (Collins 2012) arguably demonstrates the most overt and conscious incursion into this area to date. It specifically interrogates how the filmic representation of the psychogeography and soundscape of the Irish rural landscape can serve to express emotion, alienation and nostalgia, thus confronting both the Irish landscape and the weight of its associated history